Lung cancer is the most common human neoplasm in the U.S. and, increasingly, in much of the world. While smoking is known to be the major etiological factor, the causative cellular and molecular mechanisms are complex and not well understood. Currently, we are focusing on two aspects of causation and behavior of adenocarcinoma, the most common form of lung cancer: the role of the K-ras gene; and contributions of a signaling pathway triggered by the ErbB3 receptor. The oncogene K-ras is often mutated in adenocarcinoma of the lung (as well as other common carcinomas), but the wild-type form is tumor suppressive. Important questions, then, are: why is mutant K-ras actively oncogenic? How is wild-type K-ras tumor suppressive. Answers to these questions could aid in prevention of up to 50% of human lung adenocarcinomas, and an even higher percentage of cancers of the colon and pancreas. We have found stable transfection of mutant K-ras in lung epithelial cells, with moderate increase in activity, results in upregulation of cyclooxygenase 2, peroxide generation, and DNA damage, which can be blocked with a COX2 inhibitor. Inducible expression of mutant K-ras at high activity leads to generation of both peroxide and superoxides, followed by upregulation of anti-oxidant defenses, especially peroxiredoxins. Abrogation of these defenses by chemicals such as those found in tobacco smoke may lead to cell transformation; this is under test. These results support use of antioxidants for prevention/intervention of lung cancer. Mechanisms of regulation of wild-type K-ras in nontransformed lung epithelial cells are also under study; early results implicate the epidermal growth factor receptor.In the second aspect of this project, the majority of human and mouse lung adenocarcinoma cell lines, but not nontransformed cells, express the ErbB3 receptor, which signals through phosphatidylinositol 3-kinase, Akt, GSK3beta, and cyclin D1 to stimulate the cell cycle and also cell invasiveness and migration. These behaviors can be blocked with siRNA to ErbB3 or the several Akt isoforms. Thiu, siRNA treatment may be an approach to therapy. Tests with xenografts are in progress.